VCV003062334.1 - ClinVar

NM_033395.2(CEP295):c.163_164del (p.Arg55fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033395.2(CEP295):c.163_164del (p.Arg55fs)

Variation ID: 3062334 Accession: VCV003062334.1

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 11q21 11: 93667659-93667660 (GRCh38) [ NCBI UCSC ] 11: 93400825-93400826 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 30, 2024	Mar 30, 2024	Mar 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033395.2:c.163_164del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_203753.1:p.Arg55fs	frameshift
NC_000011.10:g.93667659AG[1]
NC_000011.9:g.93400825AG[1]

Protein change

R55fs

Other names

Canonical SPDI

NC_000011.10:93667658:AGAG:AG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 617728.0003 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CEP295		-	-	GRCh38 GRCh37	214	237

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Seckel syndrome 11	Pathogenic (1)	no assertion criteria provided	Mar 22, 2024	RCV003986068.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 22, 2024)	no assertion criteria provided Method: literature only	SECKEL SYNDROME 11 Affected status: not provided Allele origin: germline	OMIM Accession: SCV004801896.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 38154379 Comment on evidence: In a 4.5-year-old Hispanic girl (patient 2) and her 3-month-old monozygotic twin brothers (patients 3 and 4) with Seckel syndrome-11 (SCKL11; 620767), Li et al. … (more) In a 4.5-year-old Hispanic girl (patient 2) and her 3-month-old monozygotic twin brothers (patients 3 and 4) with Seckel syndrome-11 (SCKL11; 620767), Li et al. (2024) identified compound heterozygosity for mutations in the CEP295 gene: a 1-bp deletion (c.163_164del, NM_033395.2) in exon 3, causing a frameshift predicted to result in a premature termination codon (Arg55GlufsTer49) within the DDC8-like domain, and a c.1685C-T transition in exon 14, resulting in a pro562-to-leu (P562L) substitution. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in an in-house database of approximately 12,000 exomes; both variants were present at low minor allele frequency in the gnomAD database, only in heterozygous state. To assess the pathogenicity of the P562L missense variant, the authors studied transfected fibroblasts derived from patient 1 (see 617728.0001) and observed that wildtype CEP295, but not the P562L mutant, could correct the centrosomal and ciliary defects present and restore the defects of PLK4 (605031) recruitment. The authors concluded that the P562L variant significantly impairs the function of CEP295. (less)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities.	Li N	EBioMedicine	2024	PMID: 38154379

Text-mined citations for this variant ...

Record last updated May 12, 2024

ClinVar Genomic variation as it relates to human health

NM_033395.2(CEP295):c.163_164del (p.Arg55fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...